Objective To evaluate the influence of the mitochondrial DNA (mtDNA) haplogroups in the risk of incident knee osteoarthritis (OA) and to explain the functional consequences of this association to identify potential diagnostic biomarkers and therapeutic targets.
Methods Two prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 2579 subjects of the incidence subcohort, and the cohort hip and cohort knee (CHECK) included 635, both with 8-year follow-up. The analysis included the association of mtDNA haplogroups with the rate of incident knee OA in subjects from both cohorts followed by a subsequent meta-analysis. Transmitochondrial cybrids harbouring haplogroup J or H were constructed to detect differences between them in relation to physiological features including specific mitochondrial metabolic parameters, reactive oxygen species production, oxidative stress and apoptosis.
Results Compared with H, the haplogroup J associates with decreased risk of incident knee OA in subjects from OAI (HR=0.680; 95% CI 0.470 to 0.968; p<0.05) and CHECK (HR=0.728; 95% CI 0.469 to 0.998; p<0.05). The subsequent meta-analysis including 3214 cases showed that the haplogroup J associates with a lower risk of incident knee OA (HR=0.702; 95% CI 0.541 to 0.912; p=0.008). J cybrids show a lower free radical production, higher cell survival under oxidative stress conditions, lower grade of apoptosis as well as lower expression of the mitochondrially related pro-apoptotic gene BCL2 binding component 3 (BBC3). In addition, J cybrids also show a lower mitochondrial respiration and glycolysis leading to decreased ATP production.
Conclusions The physiological effects of the haplogroup J are beneficial to have a lower rate of incident knee OA over time. Potential drugs to treat OA could focus on emulating the mitochondrial behaviour of this haplogroup.
- Knee Osteoarthritis
- Gene Polymorphism
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FJB and IR-P contributed equally.
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Contributors FJB and IR-P contributed equally in the design and coordination of the study; both conceived the study, participated in its design and helped to draft the final version of the manuscript; MF-M carried out the cybrid experiments and helped to draft the manuscript and data interpretation; AS-H carried out the experimental procedures of mitochondrial haplogroup assignment; MEV-M, EC-P, SR and TH-G helped to carry out the cybrids cell culture, the subsequent experimental procedures and the haplogroup assignment; SP supervised the statistical procedures; NO-V and CF-L helped the understanding of the clinical and radiological variables included in the different OAI and CHECK datasets; RG provided the necessary infrastructure for the development of the transmitochondrial cybrids. All the authors approved the final version of the manuscript.
Funding This study was supported by grants from Fondo de Investigación Sanitaria CIBERCB06/01/0040-Spain, RETIC-RIER-RD12/0009/0018 and PI14/01254, integrated in the National Plan for Scientific Program, Development and Technological Innovation 2013–2016 and funded by the ISCIII-General Subdirection of Assessment and Promotion of Research-European Regional Development Fund (FEDER) ‘A way of making Europe’. IRP is supported by Contrato Miguel Servet-Fondo de Investigación Sanitaria (CP12/03192).
Competing interests None declared.
Patient consent Obtained.
Ethics approval National Institutes of Health and Dutch Arthritis Association.
Provenance and peer review Not commissioned; externally peer reviewed.
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